Available online at … · Ahmed Shawky Mohamed Ghanem*, Dr. Hany Saleh Mohamed Ali, Dr. Sohair Mostafa El-Shanawany, Dr. El-Sayed Ali Ibrahim Faculty of Pharmacy, Assiut University,

Ghanem et al . / IJDFR volume 3 Issue 6, Nov-Dec .2012

68 Ghanem et al / IJDFR volume 3 Issue 6, Nov-Dec .2012

Available online at www.ordonearresearchlibrary.org ISSN 2229-5054

INTERNATIONAL JOURNAL OF DRUG FORMULATION AND RESEARCH

SOLUBILITY AND DISSOLUTION ENHANCEMENT OF QUERCETIN VIA PREPARATION OF ROTARY SOLVENT EVAPORATED AND FREEZE DRIED TERNARY SOLID DISPERSIONS

Ahmed Shawky Mohamed Ghanem*, Dr. Hany Saleh Mohamed Ali, Dr. Sohair Mostafa El-Shanawany, Dr.

El-Sayed Ali Ibrahim Faculty of Pharmacy, Assiut University, Egypt.

Received: 11 Oct. 2012; Revised: 5 Nov. 2012; Accepted: 12 Dec. 2012; Available online: 5 Jan. 2013

INTRODUCTION

Quercetin [QC] is one of the most prominent antioxidants [1]. In spite of its wide spectrum of

bioactivity including antiviral [2], anticancer [3], antiinflammatory [4] and hepatoprotective actions [5], its

therapeutic benefits is still limited because of its poor bioavailability [6] due to its poor solubility and

limited dissolution [7]. Therefore, an efficient oral formulation of QC with an enhanced dissolution rate and

hence, an improved bioavailability is highly desired.

Various techniques have been used in an attempt to improve solubility and dissolution rates of poorly

soluble drugs which includes solid dispersion, micronization, lipid based formulations, liquisolid compacts, and

complexation [16]. Lately, a few attempts to enhance QC bioavailability have been reported in the literature.

Indeed, it was proven that QC dissolution rate could be enhanced by complexation with cyclodextrins [17],

development of biodegradable nanoparticles [18], and preparation of QC liposomes [19]. However, instability

problem implicates the usefulness of these preparations.

The solid dispersion technique for water-insoluble drugs provides an efficient method to improve the

dissolution rate of such drugs [20,21]. In solid dispersion systems, a drug may exist as an amorphous form in

Research Article

ABSTRACT Quercetin (QC), a naturally occurring antioxidant drug has wide range of pharmacological activities. However, its limited aqueous solubility and dissolution restrict its bioavailability. Ternary solid dispersions (TSD) of QC in different ratios with hydrophilic carriers such as PVP K30 and PF 127 were prepared by freeze drying (FTSD) and rotary solvent evaporation (RTSD) techniques. The prepared dispersions were evaluated for solubility and dissolution in comparison to that of their physical mixtures and the drug powder. The aqueous solubility of QC powder was favored by formation of TSD with polyvinylpyrrolidone K30 (PVP K30) and pluronic F 127(PF 127), and improved from 7.6 ± 0.8 mg/l for QC to 256 ± 4.0 and 240 ± 0.75 mg/l for RTSD and FTSD respectively. The high solubility of QC from TSD could contribute to the enhanced dissolution, as the percent of QC dissolved at 300 min. (% D300min) increased from 33 for QC to 96.74 for RTSD and 85.9 for FTSD. Solid state characterization of TSD system using XRPD, FTIR, DSC and SEM techniques revealed distinct loss of drug crystallinity in the formulation, thus accounting for enhancement in dissolution rate. Keywords: Ternary solid dispersions, quercetin, freeze drying, solvent evaporation, dissolution, solubility.



polymeric carriers such as PVP and pluronics® , and this may result in improved solubility and dissolution rate

as compared with crystalline material. The mechanisms for the enhancement of the dissolution rate of solid

dispersions have been proposed by several investigators. Drugs molecularly dispersed in polymeric carriers may

achieve the highest levels of particle size reduction and surface area enhancement, which result in improved

dissolution rates [22]. Furthermore, drug solubility and wettability may be increased by surrounding hydrophilic

carriers [23].

Freeze drying also known as lyophilization has been thought of as a molecular mixing technique

where the drug and carrier were co-dissolved in common solvent, frozen and then sublimed under vacuum

to obtain a lyophilized molecular dispersion [24].

The present study aimed to improve the solubility and dissolution of QC, a poorly soluble

bioflavonoid, via dispersion of the drug through the matrices of various hydrophilic carrier systems using

rotary solvent evaporation and freeze drying techniques.

2. Materials and methods

2.1. Materials

Quercetin; (QC, MW 338.27 g/mol, E. Merck, F.R. Germany), Ethanol (Alamia Pharm. Chem. Co.,

Egypt), Pluronics® F 127 (PF 127) (Sigma-Aldrich Chem.,Germany), Polyvinylpyrrolidone (Povidone, PVP

K30), Polyethylenedodecylether (Brij® 35, Merck, Germany).

2.2. Methods

2.2.1. Preparation of rotary solvent evaporated ternary solid dispersions (RTSD)

RTSD composed of QC/PVP K30 (1:3 w/w) and different proportions of PF 127 (1,3,5,7,10 %w/w)

were prepared by dissolving an accurately weighed amount of PVP K 30, and PF 127 in appropriate amount of

water, QC was dissolved in the appropriate amount of ethanol. The ethanolic solution of QC was added to the

aqueous polymer solution, and stirred for 15 min. The solvent was then evaporated under reduced pressure at 50

ºC by rotovapor (Buchi, Switzerland). The co-evaporates removed from the flask and stored in a desiccator for

24 h. Subsequently, the dispersion was ground in a mortar and passed through a 150 µm sieve, and the drug

content was determined spectrophotometrically at 256 nm.

2.2.2. Preparation of freeze dried ternary solid dispersions (FTSD)

FTSD composed of QC/PVP K30 (1:3 w/w) and different proportions of PF 127 (1,3,5,7,10 %w/w)

were prepared by dissolving an accurately weighed amount of PF 127 and PVP K30 in a sufficient amount

of water. QC was dissolved in the appropriate amount of ethanol. Then the drug solution was added to the

polymer solution, and stirred for 15 min. The solution was frozen overnight and then lyophilized over period



of 48 h using freeze-drier (IL SHIN LABCO. LTD, FD5508, Korea), free-zone – 40 ±1.0 ◦C with 5 mtorr

vacuum for 48 h. The dry products were removed from the containers, effort being made to minimize the

loss, then transferred to glass desiccators and dried for 24 h. This was followed by grinding in a laboratory

mortar and deagglomeration through a 150 µm sieve... The QC content in the freeze dried powder was

determined spectrophotometrically at 256 nm.

2.2.3. Preparation of Physical mixtures

QC, PVP K 30, and PF 127 were accurately weighed, pulverized and then mixed thoroughly by light

trituration during 3 min in a mortar until a homogeneous mixture was obtained. The mixture was passed through

a 150 µm sieve (mesh no. 100). In this way physical mixtures containing different weight ratios of the drug to

the polymer were prepared.

2.2.4. Solubility studies

The solubility of the prepared formulations was assessed in distilled water at 37 °C by adding an excess

of the powder (50 mg) into a 10 ml screw- capped glass vial containing 5 ml of distilled water (pH 5.8). The

samples were placed on a shaker (Gesellschaft labor technik m.b.h. &Co., Germany), and agitated at 50 rpm at

37 °C for 24 h which was previously found to be adequate time for equilibration. An aliquot of each solution

was then withdrawn and filtered through a 0.45 µm pore size membrane filter (Millipore, Switzerland), and

appropriately diluted. The assay of QC was determined spectrophotometrically at 256 nm. Each test was

performed in triplicate and the means of the three experiments were determined.

2.2.5. Dissolution studies

Dissolution studies were performed using USP XXIV (USP, 2000) dissolution apparatus II (Paddle

type). Samples equivalent to 25 mg of QC were added to the dissolution medium (900 ml of distilled water,

containing 0.1% Brij® 35 at a temperature of 37°C), which was stirred with a rotating paddle at 100 rpm. At

time intervals; 10, 20, 30, 40, 50, 60, 90, 120, 150, 180, 240, and 300 min., 5 ml samples were withdrawn,

filtered (0.45 µm), and analyzed with UV-spectrophotometer at λ 256 nm. The same volume of fresh medium

was added to replace the withdrawn sample and the correction for the cumulative dilution was calculated. Each

test was performed in triplicate and the average percent dissolved of the drug was plotted against time.

2.2.6. Scanning electron microscopy (SEM)

Size and surface morphology of QC, PVP K30, PF 127, PM, RTSD and FTSD particles was examined

by scanning electron microscope. Samples were gold sputter-coated to render them electrically conductive and

then eventually observed at different extensions (Jeol JSM-6400 LV. SEM, Japan)..



2.2.7. FTIR spectroscopy

Fourier transform infrared spectra were obtained using a Thermo Scientific FTIR. Samples of QC, PVP

K30, PF 127, PM, RTSD and FTSD were analyzed as KBr discs in the spectral region 650-4000 cm-1.

2.2.8. X- ray diffraction

The physical state of QC in the different samples was evaluated with X-ray powder diffraction.

Diffraction patterns were obtained on a X-ray generator PW 1050 diffractometer using Cu Kα radiation (λ =

1.54184 A˚). Drug samples were scanned over an angular range of 2-60º 2θ, with a step size of 0.06°, and a

count time of 1 min per step (scanning speed 0.06/min). The generator was set to 35 kV and 40 mA.

2.2.9. Differential scanning calorimetery (DSC) analysis

Samples of each of QC, PVP K30, PF 127, PM, RTSD and FTSD were analyzed by differential

scanning calorimetry (DSC-T50%, Shimadzu, Japan) calibrated with indium (99.9% purity, m.p. 156.6 ºC).

Thermograms were recorded by placing accurately given quantities; five milligram in aluminum crimped pans,

samples were heated from 30-350 ◦C at a scanning rate of 10 ◦C/min under nitrogen gas flow at rate of 20

ml/min.

3. Results and discussion

The UV analysis performed on the prepared TSD showed in all cases high values of drug loading

ranging from 92 ± 1.1 to 99 ± 1.8%.

3.1. Solubility studies

In order to improve the solubility and dissolution properties of QC, several solid dispersion formulations

consisting of QC, PVP K30 and PF 127 were investigated. The selection of the polymers and the surfactants is

based on the assumption that one must dissolve the drug in the solid state (PVP K30), leading to a stable system

without phase separation, while the other one must increase the solubility and dissolution of the drug (PF 127).

As summarized in Table I, the solubility of QC was markedly enhanced in TSD as the proportions of

PF 127 were increased. Given that all the samples used in this study had the concentration of PF 127 higher

than its critical micelles concentration (CMC) (0.021%, w/w), there should be simultaneous increase in

micelle concentration along with the increase in concentration of PF 127. Additional information on the

effect of the two carries toward QC was obtained by DSC, FT-IR, XRD and SEM. This can be explained by

the difference of the physical behavior of QC in each case. As in case of TSD, QC dispersed at molecular level

in the carrier matrix, or it exists as amorphous solids, however in PMs, soluble complex might be prominent.



3.2. Dissolution studies

3.2.1. Dissolution study of RTSDs

The improved dissolution characteristics QC from RTSD prepared from QC/PVP K 30 (1:3) and 1, 3, 5, 7,

10 %w/w of PF 127 were evident in Fig. 1 , in comparison with the QC and PM (Fig. 2). The percent of QC

dissolved after 5 h (%D300min= 33 for QC, and 46.8 for PM 1:3:10%) confirming the inherent low dissolution of

QC. While %D300min were 73.84, 75.8, 85.83, 87.8, and 96.74 % from RTSDs composed of 1:3:1%, 1:3:5%,

1:3:7%, and 1:3:10% QC : PVP K30 : PF 127, respectively. This dissolution enhancing behavior of RTSD may

be explained on the basis of increased QC–water interaction, and, wettability due to the presence of carries in

addition to amorphization of QC.

3.2.2. Dissolution study of FTSD

. All FTSD showed better dissolution rate than QC as shown in Fig. 3. However, it is interesting to

note that at different PF 127 concentrations 1,3,5,7,and 10%, the %D300min values for all formulations were

very much similar. The value of %D60min for QC (23.7) was enhanced to be 60.8, 61, 62.4, 62.7, and 63.5 for

FTSDs containing 1, 3, 5, 7, and 10 % w/w of PF 127 respectively. This can be attributed to greater

hydrophilicity and surfactant property of the polymers, results in greater wetting and increases the surface

available for dissolution, by reducing interfacial tension between he hydrophobic drug and the

dissolution medium.

3.3. Physical characterization

Physical characterization of MTSD by SEM, FTIR, DSC, and XRPD, in comparison with corresponding

physical mixtures, was done to establish the possible mechanism responsible for the observed great increase of

solubility and dissolution of QC from TSD

3.3.1. SEM

SEM microphotographs (Fig. 4) show QC in a crystalline state with a needle shape, PM showed particles

of PVP K30 and PF 127 embedded with QC needle crystals. It seems to observe particles of FTSD exhibited

rod shape, lack of uniformity in size and shape. RTSD is observed as rose-like or irregular shaped crystals. The

change in the morphology and shape of particles was observed in RTSD, and FTSD revealing an apparent

interaction in the solid state.



3.3.2. XRPD

The representative X-ray diffraction patterns of the raw QC powder, and its TSD (RTSD and FTSD)

with PVP K30 and PF 127 at 1:3:10% ratio and their corresponding PM at the same ratio are shown in Fig.

5 and 6. It can be seen that the raw QC powder exhibits major peaks at a diffraction angle 2θ = 10.78◦,

12.46◦, 15.88◦, and two more prominent peaks at 25.66◦, and 27.4◦. PVP K30 is nearly amorphous as indicated

by its diffraction spectrum without prominent peaks. PF 127 is semi-crystalline and exhibits two sharp

diffraction peaks at 2θ = 19.42◦ and 23.5◦. Comparing the prepared TSD, with their corresponding PM, it

can be observed that QC peaks are absent in the TSD, while drug crystallinity peaks were still detectable in

the respective PM. According to these results, the complete absence of diffraction peaks corresponding to

the crystalline drug, indicates that a total drug amorphization was instead induced by RTSD and FTSD.

3.3.3. DSC

QC is a dihydrate molecule and in the DSC curve it showed a broad endothermic peak (Tpeak = 101 ◦C) as it

becomes anhydrous and a melting endotherm (Tonset = 322.8 ◦C; Tpeak = 326.2 ◦C). Liberation of crystal water

from PVP K30 was observed as a broad endothermal peak at 70 ◦C. And PF 127 had endothermic peak at 60

◦C. (Fig. 7 and 8). The absence of the melting peak for QC in the thermal profiles of RTSD and its PM

confirmed that QC was well embedded in the polymeric matrices, as also shown by SEM and X-ray analyses.

Moreover, absence of new peaks suggested that no chemical interactions occurred between the carriers and QC.

Only thermal profiles for both RTSD and its PM, show two melting peaks, one sharp peak shifted to lower

temperature (from 60◦C to 53 ◦C) for PF 127 , and other broader peak for PVP K30 shifted to higher

temperature (from 70◦C to 80 ◦C), suggesting some sort of physical interaction.

The characteristic, well recognizable thermal profile of the drug at the temperature corresponding to its

melting point disappeared in both PM and FTSD (Fig. 8). This phenomenon can be assumed as proof of

interactions between the components of the respective ternary systems or drug amorphization.

3.3.4. FTIR spectroscopy

The spectrum of QC showed characteristic bands of the OH group which were found at 3550 cm-1. The

carbonyl stretching mode appears as a very strong doublet at 1650 cm-1 and 1640 cm-1. Other characteristic

bands were found at 1300 cm-1 (C–OH stretch). The spectrum of PVP K30 showed important bands at 2953

cm-1 (C–H stretch) and 1652 cm-1 (C=O). A very broad band was also visible at 3546 cm-1 which was attributed

to the presence of water confirming the broad endotherm detected in the DSC experiments.

FTIR spectra of the prepared RTSD, and FTSD did not show any difference in the peak patterns with

respect to raw material, and their PM (Fig. 9 and 10), indicating the lack of chemical interaction between QC



and carriers (PVP and PF 127). Only decreased intensity in OH band (3550 cm-1) could be observed,

confirming that some physical interactions occur between QC and the carriers. According to literature [25-27],

in some conditions hydrophobic phenyl aglycones can just bind with polymer molecules through intermolecular

H-bond with their hydroxyl-groups.

4. Conclusion

Ternary solid dispersions (TSD) of QC with PVP K30 and PF 127 were prepared to enhance QC

solubility and dissolution by using freeze drying and rotary evaporation process. Both FTSD and RTSD

formulations showed increased solubility and dissolution over the drug powder and PM.. the improvement of

solubility and dissolution was attributed to amorphization of the drug in carrier matrix, in addition to improved

wettability of the drug and minimization of agglomeration caused by the hydrophilic carriers. Thus, TSD would

be a potential candidate for delivering the poorly water-soluble QC with enhanced solubility and dissolution.

This system which made up of QC/PVP/PF 127 in ratio of 1: 3:10 % respectively, can be used for the oral solid

dosage form development in order to be commercialized.

Acknowledgment

This study was supported by Pharmaceutics Department, Faculty of Pharmacy, Assiut University, Egypt.

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Figures

Fig. 1

Fig. 2

0

10

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30

40

50

60

70

80

90

100

0 50 100 150 200 250 300

QC

1:3:1%

1:3:3%

1:3:5%

1:3:7%

1:3:10%

0

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0 50 100 150 200 250 300

QC

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1:3:3%

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Time ( min)

% D

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Fig. 3

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Fig. 4

Fig. 5

Fig. 6

Degree (2θ)

Inte

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Inte

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Fig. 7

Fig. 8



Fig. 9



Fig. 10



List of figures:

Fig. 1: Dissolution profiles of various RTSD [QC-PVP-PF 127] in 900 ml water containing 0.1 % Brij® 35 (

pH 5.8, 37 ºC).

Fig. 2: Dissolution profiles of various PM [QC/PVP/PF 127] in 900 ml water containing 0.1 % Brij® 35 (

pH 5.8, 37 ºC).

Fig. 3: Effect of various PF 127 concentrations on the dissolution profiles of QC (25 mg) from FTSDs in

900 ml water containing 0.1 % Brij® 35 ( pH 5.8, 37 ºC).

Fig. 4: SEM photographs of : A- QC, B- PM, C- 1:3:10% RTSD, D- 1:3:10% FTSD.

Fig. 5: X-ray diffractograms of: QC (A), PF 127 (B), PVP K30 (C), 1:3:10% PM (D), 1:3:10% RTSD (E).

Fig. 6: X-ray diffractograms of: QC (A), PF 127 (B), PVP K30 (C), 1:3:10% PM (D), 1:3:10% FTSD (E).

Fig. 7: DSC thermograms of: QC (A), PVP K30 (B), PF 127 (C), QC/PVP/P F127 1:3:10% PM (D),

QC/PVP/P F127 1:3:10% RTSD (E).

Fig. 8: DSC thermograms of: QC (A), PVP K30 (B), PF 127 (C), 1:3:10% PM (D), 1:3:10% FTSD (E).

Fig. 9: FTIR-spectra of: A- QC, B- PVP K30, C- PF 127, D- QC/PVP/PF 127(1:3:10%) PM, E- QC/PVP/P F

127(1:3:10%) RTSD.

Fig. 10: FTIR- spectra of: A- QC, B- PVP K30, C- PF 127, D- QC/PVP/PF 127(1:3:10%) PM, E- QC/PVP/ PF

127(1:3:10%) FTSD.



Table I: Solubility of different TSD formulations composed of QC/PVP K30 (1:3) and different

proportions of PF 127 (1, 3, 5, 7, 10%w/w) and the corresponding physical mixtures (mean ± S.D., n =

3).

Formulation (w/w)

QC:PVP K30:PF 127

Solubility (mg/l)

RTSD FTSD PM

1:3:1%

1:3:3%

1:3:5%

1:3:7%

1:3:10%

188 ± 6.4 180 ± 0.69 130 ± 0.6

196 ± 5.1 191 ± 0.56 143 ± 0.8

203 ± 3.8 199 ± 0.38 155 ± 0.5

211 ± 2.5 202 ± 0.60 162 ± 0.9

256 ± 4.0 240 ± 0.75 165 ± 1.2

RTSD: rotary solvent evaporated solid dispersion, FTSD: freeze dried solid dispersion, PM: physical mixture, TSD:

ternary solid dispersion, PVP: polyvinylpyrrolidone, PF 127: pluronic F 127.

Documents

Available online at … · Ahmed Shawky Mohamed Ghanem*, Dr. Hany Saleh Mohamed Ali, Dr. Sohair Mostafa El-Shanawany, Dr. El-Sayed Ali Ibrahim Faculty of Pharmacy, Assiut University,